The present invention relates to a novel process for preparation of morphinane analogues i.e compounds of formula I. The morphinanes may be characterised by a common chemical structure that of a cyclic tertiary amine represented by following structure:

These analogues exert their effect at the opioid receptors in the central nervous system and other tissues and are useful as pharmaceutical substances for treatment of pain, drug abuse and various other disorders. Because of the high potency and diverse uses of the morphinane derivatives in therapy for human as well as for veterinary use, there is an increasing demand for medicinal morphinanes. Some of the morphinane analogues known in the art are as follows:

The prior known processes for preparation of the morphinane analogues generally begin with thebaine or its O-demethylated derivative, oripavine. Thebaine occurs naturally in plant sources from which it is extracted and purified by an expensive and laborious procedure. Thebaine-producing plants require special agronomical and environment conditions which can further increase the final cost of thebaine extracted thereform. Consequently, there is a need for a process of preparation of morphinane derivatives which gives high yields of quality products and which uses safer solvents and reagents.
The process for the preparation of morphinane derivatives comprises mainly of two steps starting from thebaine or oripavine namely the N-demethylation and N-alkylation. The following patent references generalize the state of art for the N-dealkylation of thebaine or oripavine.
U.S. Pat. No. 3,433,791 (as referred to as '791) discloses endoethano northebaine and nororipavine derivatives, including, N-cyclopropylmethyl-6,14-endoethano-7-(2-hydroxy-2-methyl-2-tertbutyl)-tetrahydronororipavine commonly known as Buprenorphine. The '791 patent describes N-demethylation of endoethano thebaine and oripavine derivatives in a two step process, first step involving formation of N-cyano derivative using cyanogen bromide followed by hydrolysis of the N-cyano derivative to yield the N-demethylated product. The process gives a lower yield (˜70%) of the N-demethylated product and further requires the use of cyanogen bromide, which is toxic and requires great precautions for use in large scale. The following scheme 1 outlines the process of preparation of buprenorphine as disclosed in the '791 patent.

Canadian Patent No. 2597350, discloses preparation of noroxymorphone derivatives like naltrexone and naloxone. It discloses N-demethylation of noroxymorphone using ethyl chloroformate in presence of basic conditions to prepare noroxymorphone carbamate which is hydrolyzed to form the N-demethylated derivative. More specifically, it describes the N-demethylation of diacetyloxymorphone to form diacetyloxymorphone carbamate, which is then hydrogenated to yield noroxymorphone i.e. the N-demethylated derivative. The yield of the N-demethylated product is ˜65% based on the starting material used. Further, European Patent No. 164290 discloses a similar process for preparation of 14-hydroxymorphinanes with lower yields. It was found by us that with the use of ethylchloroformate for N-demethylation of compounds of formula I of the present invention, the reaction did not go to completion and the yields obtained were lower.
Also, U.S. Pat. No. 4,141,897 discloses use of vinyl chloroformate for N-demethylation of N-alkyl-14-hydroxymorphinans, however, the process suffers from disadvantages in that the yield obtained is 70-85%, the instability of the reagent leads to variable output and its delicate preparation requires high cost.
The process of present invention does not use toxic reagents like cyanogen bromide for N-demethylation, instead uses an C1-4alkylchloroformate along with an alkali iodide and a heterogenous base, for the N-demethylation of thebaine or oripavine derivatives. The process gave higher yields, which is near the theoretically calculated value, of the N-demethylated derivative with good purity. The use of alkali iodide along with an C1-4alkylchloroformate and a base, according to the present invention, has not been disclosed heretobefore for N-demethylation of the morphinane analogues.
Further, N-alkylation of the morphinane analogues is described in several references, for example, U.S. Pat. No. 3,332,950 (referred to as '950 hereinafter), which discloses 14-hydroxydihydronormorhinones, specifically, naltrexone and methods of preparing the same. The '950 patent discloses two methods for N-alkylation of morphinane derivatives disclosed therein. In one of the methods, N-alkylation is carried out in a two-step reaction. The first step involves use of cyclopropylcarbonyl chloride to obtain a carbonylalkyl substituted compound which was subjected to reduction using lithium aluminium hydride (LiAlH4), in the second step to generate the N-alkylated compound. The method is disadvantageous in that it involves a two-step reaction for N-alkylation, uses highly reactive, pyrophoric metal hydride reagent like LiAlH4 and affords yield of approximately 33% starting from noroxymorphone. In another method (Scheme 2) 14-hydroxydihydronormorphinone is treated with cyclopropylmethyl bromide in DMF to prepare naltrexone. The method employs high temperatures and prolonged reaction time (7 days) yet achieves only a 60% of theoretical yield.

British Patent No. 1119270 discloses 14-hydroxydihydronormorphine derivatives such as Nalbuphine. In one of the methods disclosed therein, cyclobutylmethyl bromide is employed for N-alkylation. A similar process for preparation of buprenorphine, Naloxone and Nalorphine has been disclosed in the '791 patent, British Patent No. 939287 and U.S. Pat. No. 2,364,833, respectively, wherein the corresponding alkylhalide has been used for N-alkylation of morphinane derivatives. We have found that when the N-alkylation reaction using corresponding alkyl or cycloalkylbromide is not a clean reaction, the reaction is slow, does not go to completion and leads to an impure product. It was surprisingly found by us that the use of the corresponding alkanol, a C1-3alkyl sulfonylhalide and an alkali metal halide, in a single-step, for N-alkylation, hitherto not reported in literature for morphinane analogues, led the reaction to completion with corresponding increase in yield and quality of the product.
In addition to the N-demethylation and N-alkylation reactions, the process of preparation of a morphinane analogue, namely buprenorphine, starting from thebaine, comprises reactions for introducing endoethano bridge at the 6-& 14-position, addition of a tertiary butyl group to the carbonyl of 7-acetyl group via grignard reaction and O-demethylation reaction (See Scheme I above). The process as generically disclosed for the endoethano compounds in the '791 patent comprises reaction of thebaine with methyl vinyl ketone to form the 7-acetylendoetheno compound via a 4+2 reaction, hydrogenation of the carbon-carbon double bond of the endoetheno bridge using high hydrogen pressure, addition of a tertiary butyl group to the carbonyl of 7-acetyl group via a grignard reaction employing benzene or diethylether or a combination of these as a solvent and O-methylation reaction which is carried out at a temperature of >200° C. in presence of an alkali. Also U.S. Pat. No. 5,849,915 which discloses certain buprenorphine analogues, prepares endoetheno derivatives of morphinanes by reacting thebaine with methyl vinyl ketone in a molar ratio of about 1:1746.
The process as disclosed in the '791 and the '915 patent for preparation of buprenorphine or its precursors suffers from disadvantages, in that the process is low yielding, for example, in the '791 patent the yields of the product obtained at each step is in the range of 25-70% with the overall yield of only 4.5%. The prior art process for preparation of endoethano compounds as disclosed in the '915 patent uses a large excess of methylvinyl ketone which is not only expensive but also is lachrymatic in nature, which causes inconvenience in large scale synthesis. The hydrogenation step, as disclosed above, uses high hydrogen pressure ˜58 psi furnishing yield of only ˜60%. The grignard reaction employs a combination of benzene and diethylether as solvent, which not only gives a low yield on ˜25%, but is also not advisable because of known carcinogenicity of benzene. Further, the O-demethylation reaction requires harsh environment i.e. high temperatures in presence of an alkali which may cause an irreversible damage to the phenolic moiety as observed in poor yield, obtained for this reaction.
The process of the present invention is advantageous in that it uses of methylvinylketone in a quantity which is only four times the molar quantity of thebaine, yet furnishes a high yield of ˜90%. Further, the hydrogenation reaction is carried out at atmospheric pressure in 10% aqueous acetic acid, furnishing ˜83.0% yield. The grignard reaction of the 7-acetylated derivative, according to the present invention, avoids the toxic solvents like benzene, and instead uses solvents like tetrahydrofuran or diethylether or mixtures thereof, which are relatively safer with a 3-fold improvement in yield of the product. Further, the process uses thiols for the O-demethylation reaction and requires use of less harsher conditions of temperature, leading to a further improvement in yield.
In summary, the state of art for synthesis of morphinane analogs uses reagents and solvents which are not eco-friendly. The synthesis of the analogues involves several steps with low yields at several stages. Further the use of hazardous solvents, high pressure and high temperature reactions, prolonged reactions, contribute to the cost of production, inconsistent quality and requirement of large excess of expensive and controlled starting materials like thebaine. Thus, even though, the prior art discloses several processes for the preparation of morphinane derivatives, they have largely been unsuccessful in providing a process with high yield with safer reagents and solvents. The present invention involves steps furnishing high yields, employs stoichiometric quantities of reagents and uses class-2 and class-3 solvents which are relatively innocuous. The process of the present invention utilizes moderate reaction conditions, has reduced reaction time and furnishes high quality of the end products, all of which contribute significantly towards making the process economical. Furthermore, the process uses stable reagents and produces reproducible results.